FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphocytic leukemia
Paolo Neviani, … , John C. Byrd, Danilo Perrotti
Paolo Neviani, … , John C. Byrd, Danilo Perrotti
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2408-2421. https://doi.org/10.1172/JCI31095.
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Research Article Hematology

FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphocytic leukemia

Abstract

Blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome–positive (Ph1-positive) acute lymphocytic leukemia (ALL) are 2 fatal BCR/ABL-driven leukemias against which Abl kinase inhibitors fail to induce a long-term response. We recently reported that functional loss of protein phosphatase 2A (PP2A) activity is important for CML blastic transformation. We assessed the therapeutic potential of the PP2A activator FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride), an immunomodulator in Phase III trials for patients with multiple sclerosis or undergoing organ transplantation, in CML-BC and Ph1 ALL patient cells and in in vitro and in vivo models of these BCR/ABL+ leukemias. Our data indicate that FTY720 induces apoptosis and impairs clonogenicity of imatinib/dasatinib-sensitive and -resistant p210/p190BCR/ABL myeloid and lymphoid cell lines and CML-BCCD34+ and Ph1 ALLCD34+/CD19+ progenitors but not of normal CD34+ and CD34+/CD19+ bone marrow cells. Furthermore, pharmacologic doses of FTY720 remarkably suppress in vivo p210/p190BCR/ABL-driven [including p210/p190BCR/ABL (T315I)] leukemogenesis without exerting any toxicity. Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients.

Authors

Paolo Neviani, Ramasamy Santhanam, Joshua J. Oaks, Anna M. Eiring, Mario Notari, Bradley W. Blaser, Shujun Liu, Rossana Trotta, Natarajan Muthusamy, Carlo Gambacorti-Passerini, Brian J. Druker, Jorge Cortes, Guido Marcucci, Ching-Shih Chen, Nicole M. Verrills, Denis C. Roy, Michael A. Caligiuri, Clara D. Bloomfield, John C. Byrd, Danilo Perrotti

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Figure 6

Pharmacologic doses of FTY720 impair in vivo imatinib/dasatinib-sensitive and -resistant p210 and p190 BCR/ABL leukemogenesis.

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Pharmacologic doses of FTY720 impair in vivo imatinib/dasatinib-sensitiv...
(A) Left: Nested RT-PCR for p210 and p190 BCR/ABL indicates the presence of BCR/ABL-expressing cells in the PB of untreated and FTY720-treated mice. Nested RT-PCR performed with RNA from PB of mice treated with FTY720 only (far right lane) and with RNA from a 1:106 dilution of K562 or BaF3p190 (BCR/ABL+ cells) with 32Dcl3 cells were used, respectively as negative and positive controls. GAPDH mRNA levels were used as a control. Right panel: Visual analysis of spleens from age-matched and FTY720-treated mice and untreated and FTY720-treated mice injected with the indicated cell lines. (B) May-Grumwald/Giemsa staining of PB and H&E staining of sections from bone marrow, spleen, and liver of untreated and FTY720-treated (4 weeks) control and cell-injected mice. Original magnification, ×400 (PB and bone marrow); ×250 (liver and spleen). (C) Effect of 10 mg/kg/d FTY720 on survival of SCID mice i.v. injected with the indicated cells lines (n = 13; orange lines). Mice injected with cells only (n = 13; blue lines) or drug only (n = 13; green lines) were used as controls. The red lines below each graph indicate the treatment regimen. Survival was calculated by the Kaplan-Meier method, and the log-rank test evaluated the differences among survival distributions. Overall, P < 0.0001; 32D-p210BCR/ABL untreated versus FTY720-treated, P < 0.0001; 32D-p210BCR/ABL (T315I) untreated versus FTY720-treated, P < 0.001; and BaF3-p190BCR/ABL untreated versus FTY720-treated, P < 0.0001.